Toll-like receptors (TLR) represent the major pathway by which microorganisms interact with host cells of the innate immune system. They are a family of highly conserved class of pattern recognition receptors that recognize distinct pathogen-associated molecular patterns that are conserved in specific classes of microorganisms. Human TLR family consists of at least 10 members that can be classified into two different groups based on their cellular location. Intracellular TLR (TLR3, 7, 8 and 9) recognize nucleic acids; TLR7 and TLR8 recognize single-stranded RNA, while TLR3 and TLR9 are receptors for double-stranded RNA and DNA, respectively. In contrast, cell surface TLR (TLR1, 2, 4 and 5) recognize different components of bacteria. The expression and signaling pathways triggered by stimulating the TLR have been primarily described in antigen presenting cells (APC) that generally lead to activation of APC with inflammatory and antiviral cytokine secretion. Although predominantly studied in APC, several reports have described the expression of TLR on lymphocytes, and specifically on CD4+ T cells. As with APC, these studies indicate that TLR engagement acts as a positive costimulatory signal that increases the secretion of pro-inflammatory cytokines, proliferation and cell survival.
The innate immune system, induced by TLR signaling, is known to play a critical role in response to viral invasion. Chronic infectious viral diseases are characterized by the inability of the host immune system to mount a strong, long-lasting response against the infectious agent. In some RNA virus infections, such as hepatitis C (HCV), human immunodeficiency virus 1 (HIV-1) and human T-lymphotropic virus 1 (HTLV-1) infections, it has been shown that CD4+ T helper cell- and CD8+ cytotoxic T-cell-mediated immune responses determine the outcome of the infection, with chronic infections correlating with late, transient, weak or narrowly focused CD4+ and CD8+ T cell responses. Several studies have demonstrated that there is impairment with activation and/or function of T cells in HIV-1 infection. Specifically, CD4+ T cells from chronically HIV-1-infected patients display an anergic phenotype with defects in proliferation and IL-2 and IFNγ secretion
Multiple anti-viral drugs have been approved by the Food and Drug Administration to treat viral infections. These treatments focus on suppressing viral activity, but do not focus on mounting an immune response against the virus to eliminate it from the body. A need exists in the art for improved treatments and methods to improve host responses to viral infections, especially in the case of chronic viral infection.